Stress precipitates drug-seeking behavior and alters the effects of drugs of abuse. Recently our lab has demonstrated that prior exposure to ten days of chronic unpredictable stress (CUS) augments the long-term depletions of DA in the striatum produced by METH. In addition, several parallels exist between stress and the action of METH specifically with respect to the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, increases in plasma corticosterone (CORT), and elevations in body temperature. Multiple mechanisms have been implicated in METH toxicity, one being the production of free radicals. Preliminary data indicate that CUS followed by a non-neurotoxic dose of METH synergize to deplete 5HT in the hippocampus. As the hippocampus contains a high density of glucocorticoid receptors and exhibits longterm depletion of 5HT after high-dose METH, this proposal focuses on the effects of CUS and METH on the hippocampus. The overarching hypothesis is that CUS enhances the toxic effects of METH to 5HT terminals in the hippocampus via an augmentation of the CORT response to METH and an enhancement of METH-induced oxidative stress/damage.